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PubMed1990

The iC3b receptor on Candida albicans: subcellular localization and modulation of receptor expression by glucose.

Patient isolates of Candida albicans from blood, urine, or mucosal sites express a surface receptor for C3 fragment iC3b that is recognized by monoclonal antibodies (MAb) directed against alpha-chain epitopes of the neutrophil iC3b receptor, also known as the type 3 complement receptor (CR3) or CD11b/CD18. Because 60% of these patients were hyperglycemic, the effect of glucose on receptor expression was investigated. As assessed by flow cytometry, yeasts grown in 20 mM D-glucose exhibited a four- to six-fold increase in receptor expression compared with yeasts grown in 20 mM L-glutamate. Receptor expression increased as glucose concentration rose from 0 to 20 mM (equivalent to plasma glucose concentrations of 0-360 mg/dl). Augmentation of receptor expression by growth in glucose led to significant inhibition of phagocytosis compared with that of organisms grown in equimolar L-glutamate. SDS-PAGE, Western blotting, and immunodetection of extracts of yeast cell wall, membrane, and cytosol disclosed a protein of 165 kDa in membrane and cytosolic extracts, consistent with the published Mr of the alpha-chain of neutrophil CR3. These studies provide a mechanism to explain the predilection of C. albicans to infect the hyperglycemic host.

Adolescent↗
PubMed1991

Herpes simplex virus glycoprotein C is a receptor for complement component iC3b.

Herpes simplex virus type 1-infected cells bind C3b and iC3b, but not C3d, at the cell surface. Herpes simplex virus type 2 (HSV-2)-infected cells bind none of these C3 fragments. A transfection assay was used to demonstrate that binding of iC3b was to gC1. Although iC3b did not bind to HSV-2-infected cells, it did bind to mammalian cells transfected with the gC2 gene. Using linker insertion mutants, three domains on gC2 that are important for binding iC3b were mapped; these regions were similar to previously defined regions involved in binding C3b. These results suggest that some of the functions served by gC may be similar to those of CR3, the mammalian receptor for iC3b.

Amino Acid Sequence↗
PubMed1994

Binding of human immunodeficiency virus type 1 to the C3b/C4b receptor CR1 (CD35) and red blood cells in the presence of envelope-specific antibodies and complement. National Institutes of Health AIDS Vaccine Clinical Trials Networks.

Immune complexes formed in vitro by incubating cell-free human immunodeficiency virus type 1 (HIV-1) with sera from infected or gp160-vaccinated persons, together with normal human serum as a source of complement, readily bound to K562 cells expressing recombinant human complement receptor type 1 (CR1). However, antibodies from seronegative persons had little or no effect. This effect was absent in the presence of heat-inactivated or C3-depleted normal human sera or when wild type K562 cells were used, confirming a requirement for complement and CR1. In additional experiments, complement alone targeted HIV-1 to CR1 on red blood cells, and envelope-specific antibodies increased this effect. These results demonstrate that envelope-specific antibodies promote HIV-1 immune complex formation with complement and that these complexes readily bind CR1 on cell surfaces.

Antigen-Antibody Complex↗
PubMed1986

Solubilization of active complement receptor type 1 (CR1) from human erythrocyte stroma with trypsin and its purification.

Mild trypsinization of human erythrocyte stroma solubilized CR1 (complement receptor type 1, C3b/C4b receptor) without significant loss of decay-accelerating activity to C5 convertases on hemolytic intermediate cells (EAC 1-3b, P). The solubilized CR1 was purified using DEAE-Sephacel, C3-Sepharose, and anti-CR1-Sepharose column chromatographies. The purified material showed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under non-reducing conditions, and its molecular weight was determined to be 175K, about 20K smaller than native CR1. Because the purified sample was separated into the several segments by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, the molecule is considered to be nicked and those segments are associated by disulfide bonds. These results mean that a large portion of the CR1 molecule is present outside of the plasma membrane of erythrocytes, and the intramembranous and cytoplasmic domains are not necessary for decay-accelerating activity.

Chromatography↗
PubMed1990

Regulation of proteolytic activity of complement factor I by pH: C3b/C4b receptor (CR1) and membrane cofactor protein (MCP) have different pH optima for factor I-mediated cleavage of C3b.

C3b/C4b receptor (CR1) and membrane cofactor protein (MCP) are integral membrane glycoproteins with factor I-dependent cofactor activity. They bind to C3b, allowing factor I to cleave C3b at two sites (first and second cleavage), which results in the generation of C3bi, a hemolytically inactive form which is a ligand for complement receptor type three (CR3). C3bi is further degraded by factor I and CR1 (third cleavage) to C3dg (a ligand for complement receptor type two, CR2) and C3c. Using two different substrates, fluid-phase C3b and cell-bound C3b, the cleavage of C3b by MCP and factor I was compared to that by CR1 and factor I under various conditions. The optimal pH for the first and second cleavage of either substrate was 6.0 for MCP and 7.5 for CR1. The third cleavage was mediated only by CR1 and factor I, the optimal pH being 8.0. Low ionic conditions enhanced the C3b binding and cofactor activity of both CR1 and MCP. The efficiency of binding C3b to CR1 or MCP was maximal at pH 6.2. The isoelectric point (pI) of MCP was acidic (approximately 4.0), while that of CR1 was 6.8. Therefore, compared to CR1, MCP possesses distinct functional profiles relative to C3b-binding and factor I-cofactor activity.

Antigens, CD↗
PubMed1992

Factor I-dependent inactivation of human complement C4b of the classical pathway by C3b/C4b receptor (CR1, CD35) and membrane cofactor protein (MCP, CD46).

Proteolytic inactivation of C4b is a crucial step for regulation of the classical complement pathway. A plasma protease factor I and membrane cofactors, C3b/C4b receptor (CR1) and membrane cofactor protein (MCP), participate in the regulation of cell-bound C4b although the physiological potency of these cofactors remains unknown. We have examined the optimal conditions of the factor I-mediated C4b regulatory system using purified cofactors. CR1 being a cofactor at a cofactor/C4b ratio less than 0.1 (w/w), fluid phase C4b, and methylamine-treated C4 (C4ma) were degraded by factor I into C4bi: minimal Cd4 was generated in the fluid phase. Liposome-bound C4b (LAC4b), on the other hand, was degraded into C4c and C4d. CR1 showed two optimal pHs (6.0 and 7.5) for fluid phase C4b, but one (6.0) for LAC4b, and in both cases low conductivity conditions enhanced the C4bi generation. CR1 cofactor activity was barely influenced by the NP-40 concentration. On the other hand, MCP degraded C4b and C4ma, as a factor I-cofactor, more efficiently into C4c and C4d. Though MCP cofactor activity, like that of CR1, was enhanced under low conductivity conditions, it has only one optimal pH, 6.0, in both fluid and solid phases. Furthermore, as in the case of C3b cleavage, a sufficient NP-40 concentration to solubilize membrane was needed for MCP to express full cofactor activity for C4b, in contrast to CR1. MCP was less potent for C4b inactivation than for C3b inactivation, while CR1 acted as a slightly more effective cofactor for C4b cleavage than for C3b cleavage.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed2002

Dendritic cells in rheumatoid synovial membrane after total removal of the hyaline articular cartilage.

OBJECTIVE: To investigate the effect of total removal of the hyaline articular cartilage on dendritic cells in synovial membrane in rheumatoid arthritis (RA) or ankylosing spondylitis (AS). PATIENTS AND METHODS: Immunohistochemical staining for two dendritic cell markers, CD35 and RFD1, was carried out on synovial membrane specimens from arthritis patients undergoing primary (n=10) or revision (n=8) total hip replacement (THR). The results are expressed as the number (mean+/-standard deviation) of positive cells per 1000 total cells. RESULTS: CD35-(112+/-9) and RFD1-(27+/-5) positive cells were found in all primary RA synovial membrane, while only two out of eight synovial membrane samples from revision THR contained CD35-positive follicular dendritic cells (nine and 12 cells), and no revision samples contained any RFD1-positive interdigitating dendritic cells. CONCLUSION: Removal of the hyaline articular cartilage reduces the infiltration and functional differentiation of dendritic cells in synovial membrane. Our findings suggest that the antigen driving chronic arthritis/synovitis is contained in the hyaline articular cartilage.

Adult↗
PubMed1996

Soluble complement receptor type 1 inhibited the systemic organ injury caused by acid instillation into a lung.

BACKGROUND: Acid aspiration into one lung causes contralateral lung injury and systemic organ injury; this injury is thought to be mediated by the sequestration of activated neutrophils. Recombinant human soluble complement receptor 1 (sCR1) inhibits both the classical and alternative complement pathways; this study investigated the role of the complement system in unilateral acid lung injury by measuring the effects of administering sCR1 before or immediately after acid instillation. METHODS: Anesthetized rats (n = 18 in each group) underwent tracheostomy and insertion of a cannula into the anterior segment of the left lung. Then either 0.1 ml 0.1 N hydrochloric acid (HCl group) or 0.1 ml pH 7.4 phosphate buffered-saline (PBS group) was instilled. Fifteen minutes before (pre-sCR1 group) or 15 min after (post-sCR1 group) the acid was instilled, 10 mg/kg sCR1 was administered intravenously. Four hours after the acid instillation, rats were killed. In an additional 4 rats in each group, blood and bronchoalveolar lavage fluids obtained 1 h after the instillation of either acid or PBS were analyzed for tumor necrosis factor-alpha activity. RESULTS: The instillation of acid led to an increased wet-to-dry ratio of 5.2 +/- 0.1 in the acid-instilled lungs compared with their contralateral lungs (4.7 +/- 0.06). These values were greater than the values of 4.6 +/- 0.2 and 4.5 +/- 0.03 in the PBS-instilled lungs and their contralateral lungs, respectively (P < 0.05). The administration of sCR1 before or immediately after the instillation of acid did not attenuate the increase in the wet-to-dry ratio of the acid-instilled lungs. However, the small but consistent increase in the wet-to-dry ratio of the contralateral lungs was attenuated by the sCR1 infusions (P < 0.05). The instillation of acid increased the protein concentration in the bronchoalveolar lavage fluids from the injured lungs (1,000 +/- 206 micrograms/ml) compared with the protein concentration measured in the bronchoalveolar lavage fluids from their contralateral lungs (254 +/- 55 micrograms/ml). The administration of sCR1 before or immediately after the instillation of acid did not decrease the protein concentration in the bronchoalveolar lavage fluids from the acid-instilled lungs. The myeloperoxidase activity was increased in the acid-instilled lung, in their contralateral lung, and in the small intestines of the animals. The infusions of sCR1 before or immediately after the administration of acid led to significant decreases in the myeloperoxidase activities measured in the lungs and the intestines of the treated animals. Plasma tumor necrosis factor-alpha activity was only increased (2.7 +/- 1.1 U/ml) in the animals that had received acid instillations. The infusions of sCR1, administered either before or immediately after the acid instillations, significantly decreased the measured tumor necrosis factor-alpha activity in the plasma (0.5 +/- 0.6 and 1.0 +/- 0.7 U/ml, respectively). CONCLUSIONS: The results suggest that the complement system plays an important role in the pathogenesis of the injury of the contralateral lung and of the small intestine after unilateral instillation of acid to the lung. Further investigation is warranted to determine the clinical utility of antiinflammatory agents in acid-induced lung injury.

Acids↗
PubMed1989

Genetic analysis of CR1 (the C3b complement receptor, CD35) expression on erythrocytes of HIV-infected individuals.

The number of C3b receptor (CR1) molecules on erythrocytes is genetically determined by two codominant autosomal alleles. The genetic polymorphism of CR1 expression correlates with a Hind III restriction fragment length polymorphism (RFLP) of the CR1 gene. The relative frequency of individuals homozygous for the allele coding for low CR1 numbers is approximately 5% of the normal population. CR1 numbers/erythrocytes are significantly decreased in symptomatic HIV-infected individuals. Decreased CR1 expression correlates with the severity of disease. The present study investigated the CR1 genomic Hind III RFLP-related polymorphism in 79 HIV-infected individuals and 84 healthy subjects. Allele frequencies were found to be similar in both populations. Thus, there is no susceptibility nor resistance to HIV-infected linked to the CR1 gene. Defective expression of CR1 in HIV-infected patients is acquired through central and/or peripheral mechanisms.

Acquired Immunodeficiency Syndrome↗
PubMed1991

GM-CSF primes and modulates neonatal PMN motility: up-regulation of C3bi (Mo1) expression with alteration in PMN adherence and aggregation.

Neonatal polymorphonuclear leukocytes (PMNs) are deficient in the expression of the adherence protein C3bi (Mo1), and are associated with reduced physiological inflammatory responses. We evaluated the priming and direct stimulating effect of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) on newborn PMN expression of C3bi (Mo1), PMN adherence and PMN aggregation. Cord PMNs were incubated with rhGM-CSF (Amgen 4 x 10(7) U/mg) for 0-15 min, and C3bi surface receptor expression measured by immunofluorescence with CD11b, adherence with nylon wool, and aggregation using a Payton aggregometer. RhGM-CSF (15 min) significantly induced Mo1 expression: 250 pM/L 129.4 +/- 5.3% of C (p less than 0.001) 500 pM/L 141.5 +/- 4.1% (p less than 0.001), 1,000 pM/L 150.2 +/- 1.3% (p less than 0.0001). RhGM-CSF (1,000 pM/L x 5 min) followed by A23187 also primed newborn PMNs for increased Mo1 expression 122 +/- 4.5% of C (p less than 0.001). Additionally, rhGM-CSF (10 min) induced significant PMN adherence 50 pM/L 117.9 +/- 8.3% and 100 pM/L 131.5 +/- 5.7% of C (p less than 0.04). RhGM-CSF additionally primed newborn PMNs (100 pM/L) for increased adherence following A23187 (107.9 +/- 0.6% of C), p less than 0.02. Lastly, rhGM-CSF primed newborn PMNs for increased aggregation following FMLP: 100 pM/L, 15 min, 138.1 +/- 14.1%, p less than 0.0001. Co-incubating murine-antihuman GM-CSF AB 100 micrograms/ml neutralized 86.8 +/- 7.0% of newborn PMN Mo1 up-regulation. These studies demonstrate that rhGM-CSF primes and directly stimulates newborn PMNs for increased in vitro expression of Mo1, adherence, and aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Prospective study of the immune effects of normalizing the hemoglobin concentration in hemodialysis patients who receive recombinant human erythropoietin.

Partial correction of anemia by erythropoietin improves hemodialysis (HD)-associated immunosuppression. It is not known whether hemoglobin normalization improves immune status further. The authors prospectively compared the immune function of HD patients with congestive heart failure or ischemic heart disease on erythropoietin therapy randomized to normal versus anemic blood hemoglobin concentration. HD patients were randomized into a normal hemoglobin group (n = 17, target hemoglobin of 14 +/- 1 g/dl) or an anemic hemoglobin group (n = 18, target hemoglobin 10 +/- 1 g/dl). Delayed-type hypersensitivity, CD4 and CD8 counts, anti-tetanus toxoid antibody levels, erythrocyte complement receptor 1 expression, and lymphocyte proliferative responsiveness were measured. The observation period was 1 yr, and the trial was open label. Target hemoglobin was achieved and maintained in both groups. Significantly improved cutaneous reactivity was seen in the normal hemoglobin group (P = 0.003). The prevalence of anergy decreased in the normal hemoglobin group (from 60 to 20%) but increased in the anemic hemoglobin group (from 57 to 86%). The anemic hemoglobin group had higher CD8 counts compared with baseline (P = 0.0001) and compared with the normal hemoglobin group (P = 0.038). Both groups had significant increases in tetanus toxoid antibody levels after vaccination but without significant differences between groups. The anemic hemoglobin group had a progressive increase in erythrocyte complement receptor 1 levels compared with baseline (P = 0.002) and relative to the normal hemoglobin group (P = 0.023). There was no consistent pattern of altered proliferative responsiveness of lymphocytes. The data suggest that certain aspects of immune function, particularly delayed-type hypersensitivity, may be improved in HD patients by normalization of hemoglobin through the administration of increased doses of erythropoietin.

Aged↗
PubMed2003

Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice.

The role of intracerebral complement activation after traumatic brain injury remains unclear. In this study, the authors demonstrate that transgenic mice with astrocyte-targeted expression of the soluble complement inhibitor sCrry have a significantly reduced neurologic impairment and improved blood-brain barrier function after closed head injury compared with wild-type C57BL/6 littermates. This work further implicates the complement system as a participant in secondary progression of brain damage after head trauma and provides a strong rationale for future studies of posttraumatic pharmacologic complement inhibition.

Animals↗
PubMed1984

Inherited complement deficiencies.

Isolated genetic deficiencies of individual components of the complementary system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria. This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases--especially systemic lupus erythematosus--was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

Blood Donors↗
PubMed2003

Cloning and expression of the complement receptor glycoprotein C from Herpesvirus simiae (herpes B virus): protection from complement-mediated cell lysis.

Simian herpes B virus (SHBV) is the herpes simplex virus (HSV) homologue for the species MACACA: Unlike in its natural host, and unlike other animal herpesviruses, SHBV causes high mortality in accidentally infected humans. SHBV-infected cells, like those infected with HSV-1 and equine herpesvirus types 1 and 4, express complement C3 receptor activity. To study immunoregulatory functions involved in susceptibility/resistance against interspecies transmission, the SHBV glycoprotein C (gC(SHBV)) gene (encoding 467 aa) was isolated. Sequence analysis revealed amino acid identity with gC proteins from HSV-2 (46.9 %), HSV-1 (44.5 %) and pseudorabies virus (21.2 %). Highly conserved cysteine residues were also noted. Similar to gC(HSV-2), gC(SHBV) is less glycosylated than gC(HSV-1), resulting in a molecular mass of 65 kDa if expressed in replication-deficient vaccinia virus Ankara. Stable transfectants expressing full-length gC(SHBV) on the cell surface induced C3 receptor activity and were substantially protected from complement-mediated lysis; no protection was observed with control constructs. This suggests that expression of the gC homologues on infected cell surfaces might also contribute to the survival of infected cells in addition to decreased virion inactivation. Interestingly, soluble gC(SHBV) isolated from protein-free culture supernatants did not interfere with the binding of the alternative complement pathway activator properdin to C3b, which is similar to our findings with gC(HSV-2) and could be attributed to major differences in the amino-terminal portion of the protein with extended deletions in both gC(SHBV) and gC(HSV-2). Binding of recombinant gC(SHBV) to polysulphates was observed. This, together with the heparin-sensitivity of the gC(SHBV)-C3 interaction on the infected cell surface, suggests a role in adherence to heparan sulphate, similar to the gC proteins of other herpesviruses.

Amino Acid Sequence↗
PubMed2004

Backbone dynamics of complement control protein (CCP) modules reveals mobility in binding surfaces.

The regulators of complement activation (RCA) are critical to health and disease because their role is to ensure that a complement-mediated immune response to infection is proportionate and targeted. Each protein contains an uninterrupted array of from four to 30 examples of the very widely occurring complement control protein (CCP, or sushi) module. The CCP modules mediate specific protein-protein and protein-carbohydrate interactions that are key to the biological function of the RCA and, paradoxically, provide binding sites for numerous pathogens. Although structural and mutagenesis studies of CCP modules have addressed some aspects of molecular recognition, there have been no studies of the role of molecular dynamics in the interaction of CCP modules with their binding partners. NMR has now been used in the first full characterization of the backbone dynamics of CCP modules. The dynamics of two individual modules-the 16th of the 30 modules of complement receptor type 1 (CD35), and the N-terminal module of membrane cofactor protein (CD46)-as well as their solution structures, are compared. Although both examples share broadly similar three-dimensional structures, many structurally equivalent residues exhibit different amplitudes and timescales of local backbone motion. In each case, however, regions of the module-surface implicated by mutagenesis as sites of interactions with other proteins include several mobile residues. This observation suggests further experiments to explore binding mechanisms and identify new binding sites.

Amino Acid Sequence↗
PubMed1985

Leprosy: altered complement receptors in disseminated disease.

We have studied the expression of the C3b receptor (CR1) on erythrocytes of 55 patients with Hansen's disease. We developed a radioimmunoassay utilizing a monoclonal antibody that recognized an epitope different from the C3b binding site, which therefore enabled us to measure total number of CR1 regardless of receptor occupancy. We observed that patients in the lepromatous pole of the disease had a mean of 310 CR1/erythrocyte, whereas the ones in the tuberculoid pole showed a mean of 577 CR1/erythrocyte; 77 normal controls had a mean of 512 CR1/erythrocyte. The number of C3b receptors on the cells of lepromatous patients was significantly decreased (p less than .001) when compared to the normal population or tuberculoid patients. The presence of receptors for the C3b fragment of complement (CR1) on the surface of human erythrocytes enables these cells to participate in a number of immune functions including the clearance of circulating immune complexes. These findings could bear importance in the ability of the host to clear immune complexes from the circulation in patients with lepromatous leprosy.

Adult↗
PubMed1990

Structural and functional correlation of the human complement receptor type 1.

Human CR1 is widely distributed in the circulation as a surface receptor as well as in soluble form in the plasma. It mediates a variety of functions that include phagocytosis and regulation of the complement cascade. This receptor has been cloned and the primary structure reveals that the cell-bound molecule is an integral membrane protein with typical transmembrane and cytoplasmic domains. Its extracellular portion is composed entirely of 30 short consensus repeats (SCR) each having 60 to 70 amino acids. This type of motif is the common structural element of the superfamily of complement regulatory and receptor proteins on chromosome 1. The amino-terminal 28 SCR of CR1 is uniquely organized into four tandem long homologous repeats (LHR) with sequence homologies among corresponding SCR as high as 99%. Each LHR encodes approximately 45 kD and each except the one that is proximal to the cell surface contains a separate binding site for C3b or C4b. Analysis of the genomic structure of CR1 reveals that these LHR are results of intragenic duplication of 20- to 30-kb segments of DNA. The structural allotypes of CR1 that vary in the lengths of the polypeptides are encoded by alleles that contain different numbers of LHR. Their predicted structures would have different numbers of C3b binding sites, perhaps resulting in molecules with different capacities to bind immune complexes.

Alleles↗